Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause,and short-duration mild hypothermia is a highly effective preventive therapy

In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke. Here, our aims were to determine the importance of edema in ICP elevation after stroke and whether mild hypothermia could prevent the ICP rise. Experimental stroke was performed in rats. ICP was monitored and short-duration mild (35 °C) or moderate (32.5 °C) hypothermia, or normothermia (37 °C) was induced after stroke onset. Edema was measured in three studies, using wet–dry weight calculations, T₂-weighted magnetic resonance imaging, or histology. ICP increased 24 hours after stroke onset in all normothermic animals. Short-duration mild or moderate hypothermia prevented this rise. No correlation was seen between ΔICP and edema or infarct volumes. Calculated rates of edema growth were orders of magnitude less than normal cerebrospinal fluid production rates. These data challenge current concepts and suggest that factors other than cerebral edema are the primary cause of the ICP elevation 24 hours after stroke onset.     

Isolation of antibody to human placental alkaline phosphatase (PLAP) from extracts of human placentae

PROBLEM: Human placental alkaline phosphatase (PLAP) is a unique placental antigen bound to the syncytiotrophoblast, which may be able to elicit a specific immune response in pregnancy. METHOD OF STUDY: Antibody to PLAP was purified from placental extracts by: a) acid elution of membrane vesicles; b) purifying complexes of PLAP with human antibody on monoclonal antibodies to PLAP followed by denaturation of the enzyme; and c) by denaturation of PLAP in placental extracts and purification of antibody to PLAP on PLAP columns. RESULTS AND CONCLUSIONS: Specific antibody to PLAP is present in placental extracts, and is mostly bound to placental membrane preparations. PLAP is therefore immunogenic in pregnancy and could serve as a useful monitor of pregnancy-specific immunological responses. Since a similar enzyme appears in some cancers, it is possible that the immunization against PLAP in pregnancy will help to protect against the development of ovarian and endometrial cancer (the 'fetal antigen' hypothesis).     

Cytotoxic T-cell response to ectromelia virus-infected cells. Different H-2 requirements for triggering precursor T-cell induction or lysis by effector T cells defined by the BALB/c-H-2(db) mutation

The T(c)-cell response to ectromelia virus infection was studied in BALB/c-H-2(db) mice which carry a loss mutation in the H-2D region that results in the absence from cell surfaces of a molecule (D’) bearing certain public H-2 specificities. When infected, these mice showed a poor response of T(c) cells that recognize H-2D(d) plus virus-specific determinants on infected macrophage targets, but gave a normal response to H-2K d plus virus-specific antigens. However, their own infected macrophages do display wild-type antigenic patterns involving virus and H-2D(d) since they were killed as efficiently as wild-type (BALB/c,H- 2(d))-infected cells by T(c) cells specific only for H-2D(d) plus viral antigens. When tested in vitro, infected BALB/c-H-2(db) cells stimulated a poor T(c)-cell response to H-2D plus virus-specific antigens, but stimulated a normal response (in comparison with infected BALB/c macrophages) to H-2K(d) plus viral antigens. Uninfected BALB/c-H-2(db) cells stimulated a normal T(c)-cell response to minor H antigens or trinitrophenyl in association with H-2D(d), thus suggesting that the defective response to infection may reside in a failure of the relevant H-2D(d) antigens of mutant cells to physically associate with viral antigens. Close association of viral and H-2D-coded molecules was also suggested by ability of specific anti-H-2K or -H-2D to partially block T(c)-cell-mediated lysis of infected targets. These results were interpreted to mean that H-2Dd-dependent, virus- immune T(c) cells recognized an antigenic pattern consisting of virus- specific and H-2D(d) determinants with the latter borne on an H-2D molecule carrying serologically-defined H-2D(d) private specificities. A second H-2D(d)-coded molecule (D’) was not required for recognition and lysis by activated T(c) cells, but was apparently necessary for efficient stimulation of precursor T(c) cells, perhaps by promoting appropriate physical association of viral and H-2D(d) molecules.     

Membrane expression of platelet calpain

Platelet calpain has many platelet substrates, including external membrane proteins. We thus investigated whether platelet calpain II was associated with platelet membranes in unstimulated and thrombin- activated platelets. A monospecific, goat polyclonal antibody was reared to purified platelet calpain II. Sixteen whole platelet lysates were found to contain 4.5 +/- 0.7 micrograms calpain antigen II per 10(8) platelets (mean +/- SEM) as determined by a competitive enzyme- linked immunosorbent assay. Using the dipeptide fluorogenic substrate, Suc-Leu-Tyr-MCA, 17 human platelet lysates contained 3.6 +/- 0.4 micrograms calpain activity per 10(8) platelets. Platelet calpain II was associated with the Triton X-100 insoluble platelet cytoskeletons from both unstimulated and thrombin-activated platelets. When compared with the total cell content of platelet calpain II, calpain antigen (10% to 13%) and calpain activity (24% to 28%) was associated with platelet cytoskeletons in unstimulated and thrombin-activated platelets, respectively. On immunoblot, the heavy chain (80 Kd) of calpain II was detected in platelet cytoskeletons. Subcellular fractionation studies on both unstimulated and thrombin-activated platelets, revealed that half of the total platelet calpain II antigen was associated with cytosol, and the other half was associated with the membrane fraction. Platelet calpain II was not seen on the surface of unstimulated, paraformaldehyde fixed platelets by immunofluorescence. However, on thrombin-activated platelets, rim immunofluorescence was seen, indicating that activated platelets externalize their calpain. This observation was confirmed by the finding that about 2,000 molecules per platelet of an 125I-anti-calpain II Fab' specifically bound to thrombin-activated but not unstimulated platelets. Both dibucaine (1 mmol/L) and platelet activating factor (1.86 mumol/L) in the absence of external Ca++, but not collagen (5 micrograms/mL) or ionophore A23187 (2.5 mumol/L) in the absence of external Ca++, were also able to externalize platelet calpain II antigen, as indicated by a similar level of specific 125I-anti-calpain II Fab'-platelet binding. These combined studies indicate that platelet calpain II is a major protein, comprising 2% of total platelet protein, a substantial portion of which is membrane-associated. When platelets are activated by thrombin and platelet activating factor, calpain II antigen also becomes present on the external platelet surface.     

Are pain and function better measures of outcome than revision rates after TKR in the younger patient?

Revision is the gold standard outcome measurement for survival analyses of orthopaedic implants but reliance on revision as an endpoint has been recently questioned. This study, that assesses long-term outcome in a specific group of patients who had undergone total knee replacement (TKR) for osteoarthritis, highlights the main problems facing modern survival analyses. Minimum 12-year survival and outcome data were reviewed for a series of sixty patients under the age of 60 years (mean age 55.4 years) who underwent total knee replacement (TKR) for osteoarthritis. The patients are a subgroup from a larger consecutive series of 1429 patients who underwent TKR between 1987 and 1993 at a single institution. Whilst the main study aim was to compare outcome of TKR using different endpoints, the outcome of TKR in this younger subpopulation could also be investigated.With revision as the primary endpoint the survival for TKR was 82.2% (95% CI 17.3). The mean OKS at follow-up (mean 15.7 years) was 30.9. However, many of the 82% of patients who did not undergo revision had a less than satisfactory outcome. 41% of these patients reported modest or severe pain (using the OKS) at final follow-up. A combined endpoint including revision, poor function and significant pain drastically reduced the survival rate for the operation. Survival based on revision alone provides an acceptable but inaccurate impression of outcome in younger TKR patients (under 60 years). A true representation of the success of TKR should include pain and function as endpoints.     

No deterioration of kinematics and cruciate function 10 years after medial unicompartmental arthroplasty

The mechanisms of failure for unicompartmental arthroplasty are poorly understood. There is some suggestion that long term ligament degeneration, particularly of the anterior cruciate ligament (ACL), may affect long term survivorship. This study evaluated whether the cruciate mechanism remained functional in the long term (10 years) following UKA.

Two separate cohorts of patients who had undergone St Georg Sled medial compartmental arthroplasty had knee kinematics assessed using an established fluoroscopic technique. One group (early) was assessed at a mean of 46 months (3.8 years) since surgery, whilst the other (late) was assessed at a mean of 125 months (10.4) following surgery. No significant difference was found in the sagittal plane kinematics between the two groups or in comparison to the control normal knee.

The results suggest that after fixed bearing UKA the cruciate mechanism remains intact over time and the ligaments continue to function similarly to those of the normal knee.     

Lamotrigine for bipolar disorder and comorbid cocaine dependence: a replication and extension study

BACKGROUND: Bipolar disorder (BPD) is associated with high rates of substance abuse. We previously reported favorable results with lamotrigine in 30 patients with BPD and cocaine dependence. This report examines lamotrigine therapy in an additional 32 cocaine dependent patients. Data on these 32 participants are presented as a replication study. In addition, we extend the previous findings by combining data from both groups, and by exploring predictors of response. METHOD: Participants received a baseline evaluation and assessment for up to 36weeks with the 17-item Hamilton Rating Scale for Depression (HRSD(17)), Young Mania Rating Scale (YMRS), Brief Psychiatric Rating Scale (BPRS(18)), and Cocaine Craving Questionnaire (CCQ). Urine samples were obtained, and participants reported drug use during the previous week. RESULTS: In the replication sample (n=32), significant improvements were observed in HRSD(17), YMRS, BPRS(18), and CCQ (baseline to exit), as well as on dollars/week spent on cocaine. In the extension study, the original sample (n=30) and the replication sample (n=32) were combined for a total of 62 participants in the intent-to-treat sample. HRSD(17), YMRS, BPRS(18), and CCQ scores, as well as dollars spent on cocaine, decreased significantly. LIMITATIONS: The study has an open-label, uncontrolled design. CONCLUSION: Lamotrigine treatment was associated with significant improvements in mood, drug craving, and drug use. Controlled trials are needed.